MMP are proteolytic enzymes which play very important roles in various physiological processes, such as procreation, proliferation, differentiation, etc. Many functions of MMP are controlled by tissue inhibitors of metalloproteinases (TIMPs) under the normal physiological conditions.
MMP have a metal such as zinc in the active center, and there are known a sub-family consisting of 18 kinds (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-16, MMP-17, MMP-19, MMP-20, MMP-23 and MMP-24).
Recently it has been elucidated that when the functions of MMP are abnormally promoted, the function can not be controlled by TIMPs in the living body to cause various diseases. For example, in case of diseases relating to bone or cartilage, such as rheumatoid arthritis, osteoarthritis, etc., the amounts of glycoprotein and collagen in articular cartilage decrease due to the abnormal promotion of MMP (J. Trzaskos, et al., Acta Onthopaedica Scandinavica, 66, 150 (1995)). MMP are said to play the important roles in appearance of arteriosclerosis or re-stricturization (re-stenochoria) of post angiopoietic operation (C. M. Dollery et al., Cric Res., 77, 863 (1995)). Furthermore, MMP are known to be highly expressed in several tissues such as in mastocarcinoma tissue and therefore, it is strongly indicated that there is a possibility that MMP play the important roles in proliferation or metastasis (J. M. P. Freije et al., Journal of Biological Chemistry, Vol. 269, 16766-16773, (1994)). MMP are observed also in fibroblast isolated from the gums having inflammation (J. Periodontal Res., 16, 417-424 (1981)).
In addition, an enzyme which convert TNFα which is an exacerbation factor of inflammatory diseases from the latent type to the expression type, namely TNF converting enzyme (TACE) (Nature, 370, 555-557 (1994)), aggrecanase, and so on are within the category of MMP.
Among MMP, MMP-13 is an enzyme which localizes in joints together with aggrecanase which proteolyses aggrecan which is a main component of articular cartilage, and that shows potent proteolytic activity against collagen II which is another main component of cartilage. It is reported that MMP-13 is over-expressed in cartilage of a patient suffering from osteoarthritis (Mitchell, et al., J. Clin. Invest., 97, 761 (1996)). Such an over-expression is also observed in joints of patients suffering from bone arthritis and rheumatoid arthritis. Therefore, MMP-13 is considered as a factor relating to cartilage and bone-absorption, and it is expected that the therapeutic method by using an inhibitor of MMP-13 becomes an etiomatic therapy.
Namely, a compound inhibiting MMP-13 is considered to be useful as a prophylactic or therapeutic treating agent for arthritis such as osteoarthritis, rheumatoid, etc., and as an inhibitor of metastasis, invasion, or proliferation of various cells.
On the other hand, non-steroidal anti-inflammatory drugs (NSAID) are broadly used for treatment of osteoarthritis and rheumatoid arthritis. However, such a treatment is a symptomatic therapy, and it is desired to develop a medicament useful for etiomatic treatment such as to inhibit the progress of the diseases.
As mentioned above, it is considered that MMP inhibitors are effective for treatment and prophylaxis of the above diseases, as the promotion of the functions of MMP cause to various diseases.
As MMP inhibitors, there are reported arylsulfonamide derivatives having hydroxamic acid and so on. For example, in WO 97/27174, hydroxamic acid derivatives of α-amino acid are disclosed. In WO 99/51572 and U.S. Pat. No. 6,107,337, hydroxamic acid derivatives of α-amino acid having phenoxyphenyl as a partial structure are disclosed.
However, no compound having 4-(4-alkylsulfonylphenoxy)phenyl sulfonamide as a partial structure has been reported.
In regard to MMP inhibitors, clinical trials have been done on various compounds on cancer, rheumatoid arthritis, osteoarthritis, etc., but it is reported that many of these compounds caused side effects such as pains at skeletal muscles or joints.
MMP inhibition, such as MMP-1, MMP-14 (MT1-MMP) inhibition, is paid attention as these causes (Gendai-iryo, 32, 931 (2000), Protein, Nucleic acid and Enzyme, 45, 1083 (2000)). Among MMP knockout mice, MMP-9 and MMP-14 knockout mice indicate osteopsathyrosis. Especially, in the case of MMP-14 knockout mice, it is considered that the phenotype showed hypometabolism of connective tissue due to decrease or loss of collagen degradation ability in growth after the birth (Kenn Holmbedk et al., Cell, 99, 81-92 (1999)). Namely, it is suggested that in case of remodeling of bone or cartilage tissue the decrease or loss of collagen degradation ability occurs, and it is considered to greatly participate in the said side effect.
Therefore, it is desired to develop a MMP inhibitor having no side effects as mentioned above.